Notes
was formed by a Michael addition of ethanolamine to 3butenonitrile. Biology.$ The 11 amino alcohols showing significant antifertility activity are listed in Table I in decreasing order of potency. These compounds appear to affect fertility in at least two ways: through an arrest in development of the preimplantation embryo and by prevention of postimplantation development. Although all the active members of the series are probably capable of both actions, rather surprising differences in the antifertility profiles were observed. At lower dose levels the isopropylamino (2) and pyrrolidino (7) derivatives did not alter the number of implantation sites but did prevent postimplantation embryonic development. At higher doses the isopropylamino (2), but not the pyrrolidino (7), compound had a deleterious effect on preimplantation development and thus prevented the appearance of implantation sites. The cycloalkylamino analogs 1 and 3-5 produced only the latter effect, that of preventing the appearance of implantation sites. Further studies on the biological actions of these compounds, which are described in a separate report,8 suggest that the active members of this series of compounds possess, to varying degrees, rather specific embryotoxic effects and an action on the endometrium which precludes effective support for fetal development. These amino alcohols represent the simplest structural type yet found which possesses significant antifertility activity. Their complete lack of estrogenic or other hormonal action and the apparent duality of the antifertility effects make them attractive candidates for further study. Experimental Section# Preparation of Amino Alcohols. Method A. Reductive Alkylation. A solution of 0.70 mol of the appropriate primary amine and 0.80 mol of the desired ketone in 100 ml of absolute EtOH was treated with 0.50 g of PtO, and hydrogenated at 2 atm at room temperature until hydrogen uptake ceased (1 equiv). The catalyst was removed by filtration and the product isolated by distillation through a Vigreux column at reduced pressure. Method B. Reduction of Ethyl Oxalamides. A solution of 0.1 3 mol of the desired primary amine and 30 g of E t a in 500 ml of Et20 was added over a 20-me period to a cooled, stirred solution of 19.1 g (0.14 mol) of ethyloxalyl chloride in 300 ml of ether. The stirred mixture was allowed to warm to room temperature over the next 45 min, and the salts were then removed by filtration. The EtpO was removed under reduced pressure, and the residual oil, the ethyl oxalamide! was used directly for reduction. A solution of this oil in 300 ml of dry THF was dripped slowly into a mixture of 11.7 g (0.33 mol) of LiAlH4 (AIHS,prepared from LiA1H4 and one-third of an equivalent of AICl3, was used in some cases, especially those containing a double bond conjugated with the nitrogen atom) in 300 ml of THF, and the mixture was stirred and refluxed overnight. The reaction mixture was worked up in the usual manner, and the pure amino alcohol was obtained by distillation under reduced pressure. 2-(Isopropylamino)ethyl Hydrogen Sulfate. A cooled solution of 10.3 g of 2-(isopropylamino)ethanoI (2) in 5 0 ml of CCI, was treated slowly with 11.6 g of chlorosulfonic acid, keeping the temperature below 10". After addition was complete, the mixture was allowed to warm to room temperature and kept there for 2 hr. The precipitate was collected and recrystallized twice from 95% EtOH, affording 8.9 g of product, mp 261.5-262.5". 2-(3-Tetrahydrothienylamino)ethanol. A solution of 8.25 g of §Groups of ten female rats were given the test compounds orally o n each of the first six days of pregnancy. Day one of pregnancy
was defined as the date of mating, asverified by the presence of vaginal spermatozoa. Aqueous solutions of silts were used per se, while the pH of solutions of bases was adju:ted to 7 with HCI. The uteri were examined between days 16-1 8 of pregnancy for the presence and gross appearance of the implantation sites. Animals having one or more normal fetuses were considered t o be pregnant. #All compounds listed in the tables were characterized by microanalysis and nmr spectra. In all cases, except the two noted, the analytical figures (C, H, and N) were within acceptable limits (0.4%), and all nmr spectra were consistent with the structures and showed no extraneous peaks.
Journal of Medicinal Orernistry, 19 73, Vol. 16, No. 6
739
tetrahydrothiophen-3-one9and 4.71 g of 2-aminoethanol in 175 ml of absolute EtOH was treated with 5.07 g of sodium cyanoborohydride and 6.58 ml of 12 N HCI. The mixture was stirred at room temperature for 40 hr and then concentrated under reduced pressure. The residue was treated with K,CO, solution and extracted with EtOAc. The extract was dried over Na,SO, and concentrated. The residue was distilled twice under reduced pressure, affording 3.0 g of product, b p 87-88" (0.10 mm), which later solidified to a waxy solid, mp 41.5-46". 2-[(2,2,2-Trifluoro-l-methylethyl)amino]ethanoL A solution of 38.5 ml of 2-aminoethanol in 1000 ml of CH,Cl, was cooled to -30" and stirred while 77.2 g of trifluoroacetone was added, followed by 80 g of 4A molecular sieves. The mixture was stirred at -30" for 3 hr and then allowed to warm to room temperature and left ovenight. The filtered solution was concentrated and distilled under reduced pressure, affording 29.6 g of 2-methyl-2-trifluoromethyloxazolidine, b p 58-59" (5 mm). A solution of this oxazolidine in 50 ml of Et,O was added to a cooled solution of 7.6 g of LMIH, in 250 ml of Et,O, and the mixture was stirred overnight at room temperature. After work-up in the usual manner, the product was distilled, affording 18.0 g of amino alcohol, bp 94-95.5" (43 mm). 242-Cyano-1-methy1ethylamino)ethanol. A solution of 40.0 g of 3-butenonitrile in 100 ml of dioxane was treated with 0.30 g of KO-t-Bu and then with 45.0 g of 2-aminoethanol. The mixture was left at room temperature for 0.5 hr and then refluxed for 15 hr. The mixture was distilled under reduced pressure, affording 52.6 g of crude product, b p 122-127" (2 mm). 2-(2,2-Dimethylhydrazino)ethanol. A cooled solution of 5 0 ml of unsym-dimethylhydrazinein 150 ml of EtOH was treated with 9.9 g of glycolaldehyde and 0.3 g of p-TSA. The solution was stirred with some 4A molecular sieves for 28 hr under an atmosphere of nitrogen. The solution was then filtered, concentrated, and distilled under reduced pressure, affording 14.3 g of the dimethylhydrazone of glycolaldehyde, bp 72-73' (9 mm). A cooled solution of this hydrazone in 500 ml of absolute EtOH was treated with 8.8 g of sodium cyanoborohydride and then with 11.7 ml of 12 N HCI. The mixture was stirred at room temperature for 1 6 hr and then treated with concent:ated K,CO, solution, CH,C1,, and Et,O. The organic layer was separated and dried well over NhSO, and then over CaSO,. The solution was concentrated and distilled under reduced pressure, affording 4.0 g of product, bp 96-97" (45 mm).
References (1) West German Patent 2,105,232 (1971) [Chem. Abstr., 76, 42094h (1972)l. (2) D. D. Evans, D. E. Evans, G. S. Lewis, P. J. Palmer, and D. J. Weyell, J. Pharm. Pharmacol., 16,717 (1964). (3) D. Lednicer, S. C. Lyster, and G. W. Duncan, J. Med. Chem., 10.78 (1967). (4) M.'R. Callantine, R. R. Humphrey, S. L. Lee, B. L. Windsor, N. H. Schottin, and 0. P.,O'Brien, Endocrinology, 79,153 (1966). (5) J. J. D'Amico, M. W. Harman, and R. H. Cooper, J. Amer. Chem. Soc., 79,5270 (1957). (6) 2.J. VejdelZk, V. TrEka, H. Chybovd, and L. Ti?ma, Chem Listy, 47,49 (1953). (7) N. G. Gaylord, "Reduction with Complex Metal Hydrides," Interscience, New York, N. Y . , 1956, pp 925-930. (8) D. E. Longenecker and D. G. Gallo, Abstracts, 5th Annual Meeting of the Society for the Study of Reproduction, East Lansing, Mich., June 1972, No. 69. (9) M. Gianturco, P. Friedel, and A. S. Giammarino, Tetrahedron, 20,1763 (1964).
Local Anesthetics. Alkylthioalkyl- and Alk ylsulfiny lalkylam inoacy lanilides George H. Kronberg,* Richard S . Leard, and Bertil H. T a k m a n Research Laboratories, Astra Pharmaceutical Products, Inc., Worcester, Massachusetts 01606. Received July 13, I 9 72
In our studies of aminoacylanilides as local anesthetics we have previously reported a few alkoxyalkylaminoacylanilides.' Here we present the results of experiments with some closely related thio analogs.
740
Journal ofMedicina1 Chemistry, 1973, Vol. 16, No. 6
Notes
Local anesthetics containing open-chain thioether groups on the ultimate alkyls of the aliphatic amine moiety have been synthesized in the procaine and among cocaine-related agentsPThe thioether function has also been incorporated in rings (thiomorpholine) in the same relative position in local anesthetics of various type^.^'^ Open-chain sulfoxides have also been d e ~ c r i b e d j 9in ~ ' ~this context. Chemistry. The compounds (Tables I8 and 11) were produced as shown in Scheme I. The bromoacylanilides were Scheme I
R2 I
+ BrCOC(CH,),Br I R3
4
(Table 11)
c4
R'
X
r
(Table I)
8
" , m
y
J 'z'
C
"
$
R2 I (CH ,),N(R4)CH ,CH,SOCH
( R'
E
0040-1 0 0 0
mzm&
mmm
R3
obtained by Lofgren's acetate buffer m e t h ~ dIn . ~the case of the 0-bromo derivative 10, we observed in one run a depression of the melting point caused by admixture of the corresponding acrylanilide. This elimination product forms easily from the somewhat thermally unstable 10. The reactions between the halogenoacylanilides and the methylthioethylamines were carried out by refluxing a solution of the two reagents in the ratio 1:2.6 when the amine was primary and 1:4 in the case of secondary amines. As mentioned above, the /3-bromo derivative 10 could be expected to eliminate HBr on heating; the resulting acrylanilide, however, would react" with the primary amine forming derivative 3. Thus, the same p-amino compound will be formed regardless of whether the reaction path involves a substitution or an elimination-addition sequence. The a-bromo compound 9 , like other a-bromopropionanilides, reacted with the amines almost completely by an SN2 mechanism (no elimination reaction was observed). The a-bromoisobutyryl derivative 11 reacts quite differently, however. The presence of two methyl groups adjacent to the a-bromine promotes elimination, such that, if the amine is of suitable geometry and strength, an addition reaction will follow resulting in the formation of a mixture of a-and 0-aminoacylanilides (in the present case 4 and 5, respectively) and some acrylanilide. The 0-aminoacylanilide is obviously formed by addition of the primary amine to the acrylanilide. This was confirmed by a separate synthesis of 5 from 2'-ethylmethacrylanilide and methylthioethylamine. The separation of the a- and 0-aminoacylanilides 4 and 5 was performed according to a simple, convenient, fourfunnel countercurrent method." It should be pointed out that /3-aminoacylanilides as a rule cannot be purified by distillation because of elimination of aliphatic amine
Journal ofMedicinal Chemistry, 1973, Vol. 16, No. 6
Notes
141
Table I1
($~~CO~(CH,),,Br R' No.
R
R'
n
Yield:%
9 10
H H CH,
CH, H CH,
0
63 75c 84
11
1 0
Mp,"C 129.5-130 87.5-88 62-63
Recrystn solvent 95% EtOH Cyclohexane Petroleum ether (30-60")
Formula
Analyses
C, ,H ,,BrNO c 1,H 14BrNO C,,H ,,BrNO
H; Cb H; C@ Bre C, H
=Pure compound. bC: calcd, 51.6; found, 51.0. cUncrystauized. dC: calcd, 51.6; found, 53.0. eBr: calcd, 31.2;found, 32.2.
leading to formation of the corresponding acrylanilide. The two sulfoxides 7 and 8 were prepared as described in the Experimental Section.l2 The N-methyl-2-methylthioethylmine, previously described,' was synthesized from I-methylaziridine and methanethiol. Pharmacology and Toxicology. The compounds were tested for their local anesthetic properties on the sciatic nerve of the rat in vivo'j and the sciatic nerve of the frog in vitro. l3 Acute single-dose intraperitoneal and intravenous toxicity was determined in mice, and local tissue irritating effects were evaluated following intradermal injection into rabbits14 (see Experimental Section). The data in Table 111 summarize the result of these experiments. The anesthetic properties of the new compounds indicate that they are all inferior to lidocaine: their latency is longer, their duration is shorter, and the frequency of anesthesia obtained with them is lower. The two sulfoxides 7 and 8 closely related to 1 and 2, respectively, deviate from the latter ones in their slow rate of block on the isolated frog nerve, a slowness that is paralleled by their long latencies in the in vivo blocks. The durations of 7 and 8 are close to those of 1 and 2. Thus, this property is not appreciably altered by oxidizing the thio compounds to the corresponding sulfoxides. This structural change decreases the lipophilicity of the parent compounds. This explains their longer onset times and indicates that lipophilicity in itself is of limited importance for the duration of block. This is further illustrated by the fact that compound 6, a 2,6-xylidide, which is isomeric to 1, a 2-ethylanilide, shows increased durations at 1 and 2% over 1, although the distribution coefficient of 1 is seven times that of 6 and their p K a values are nearly equal. Whereas 2% solutions of all compounds produced low local irritation, 1 , 2 , and 4-6 were very irritating at 4% concentration. This may be a reflection of the water solubilities of the base forms." The aforesaid bases are much less water soluble than 3 , 7 , and 8. A comparison of the thioether compounds 1-6 with their oxygen ether analogst indicates that the former generally are somewhat weaker bases and much more lipophilic. On the isolated frog nerve the sulfur compounds showed a more rapid onset of blocking activity, whereas no definite trend in this respect was observed in the in vivo experiments. The durations of block in the rat sciatic nerve were the same or longer for the oxygen ethers which were also systemically more toxic but less irritating. Experimental Section A Thomas-Hoover capillary melting point apparatus was employed for all melting point determinations, and the melting points reported are corrected. Where analyses are indicated only by symbols of the elements, analytical results obtained for those elements ?A.
Brandstrom, et al., unpublished results.
were within +0.4% of the theoretical values. The microanalyses were provided by Schwarzkopf Microanalytical Laboratory, Woodside, N. Y. 2-Bromo-2'-ethylpropionanilide(9). A solution of 2ethylaniline (101.4 g, 0.837 mol) in glacial AcOH (711 ml) was cooled to 5-10' and 2-bromopropionyl bromide (201.3 g,0.932 mol) was added in one portion, mixed, and was immediately followed by a cold solution of NaOAc.3H2O (276 g) in H 2 0 (1433 ml). After shaking for 0.5 hr, the precipitate was filtered, washed (H,O), and dried. 3-Brorno-2'-ethylpropionanilide (10 ) and 2-Bromo-2'-ethyl-2rnethylpropionanilide (11). The compounds were produced in the same manner as described for 9 (Table 11). 2'-Ethylmethacrylanilide(12). The compound was prepared according t o BieberI6 (Bodroux reaction). The Grignard reagent was obtained by standard procedure from Mg (2.90 g, 0.119 g-atom) and EtBr (11.9 g, 0.109 mol) in anhydrous Et,O (50 ml). A solution of oethylaniline (12.1 g, 0.0998 mol) in Et,O (10 ml) was slowly added t o it, refluxed for 0.5 hr, followed by addition of a solution of Me methacrylate (10.0 g, 0.0957 mol) in Et,O (20 ml) over 0.5 hr, and again refluxed for 0.5 hr. After cooling (IO") and careful hydrolysis with 4 M HCl(30 ml) under vigorous agitation, the Et,O solution was successively washed (dilute HCl, dilute NaHCO,, H,O) and dried (MgSO,), and the solvent evaporated: yield 10.0 g (0.0528 mol, 55%) of colorless needles; mp 71.5-72" [petroleum ether (bp 60-110")]. Anal. (C,,H,,NO) C, H, N; mol wt: calcd, 189; found, 197. N-Methyl-2-methylthioethylamine (13)., A mixture of 1methylaziridine (Chemirad) (8.30 g, 0.145 mol) and MeSH (25.0 g, 0.520 mol) in EtOH (50 ml) was heated in an autoclave a t 60" for 96 hr. Anhydrous HC1 was passed through the reaction mixture for 0.5 hr, followed by a stream of argon (the escaping gases were passed through caustic traps). The precipitated hydrochloride (137 g, mp 131-132"; reported2 mp 128-130") was filtered, washed (Et,O), and dried. From the mother liquor another 4.0 g was obtained by evaporation and recrystallization (i-PrOH): mp 126-128"; total yield 17.7 g (0.125 mol, 86%). The salt was dissolved (concentrated ",OH) and salted out, and the freed base was extracted several times (Et,O). After the E t 2 0 extracts were dried (Na2S0,) and evaporated, the residue could be used without further purification. 2'-Ethyl-2-(2-methylthioethylamino)propionanilide(1). A mixture of 9 (12.8 g, 0.0500 mol) and MeSC2H,NH217(17.2g, 0.189 mol) in EtOH (25 ml) was allowed to reflux for 8 hr. After removal of solvent and excess amine in YUCUO, the residue was dissolved (CHClJ and extracted with 1M HCl, the combined acid extracts were washed (Et,O), the cold aqueous phase was based out t o pH 7-7.5 (7 MNaOH), and the freed base was taken up in CHCl,. After drying (Na,SO,) and evaporating the solvent, the residue was converted to the hydrochloride. 2'-Ethyl-2-(N-methyl-2-methylthioethyl~ino)propionanilide (2). A mixture of 9 (9.08g, 0.0354 mol) and 13 (9.70 g, 0.0922 mol) in C6H6(19 ml) was allowed to reflux under argon for 5 hr. The precipitated hydrobromide of 13 was filtered: wt 5.84 g (0.0314 mol, 89%); mp 77-78" (EtOH-Et,O). The residue obtained by evaporating the filtrate was worked up as described for compound 1. 2'-Ethyl-3-(N-methyl-2-rnethylthioethylamino)propionanilide (3). The compound was made using the procedure described for 2 from 10 (13.8 g, 0.0539 mol), 13 (14.7 g, 0.140 mol), and C6H6 (30 ml). The reaction product in CHCl, (25 ml total volume) was washed with phosphate buffer (five 25-ml portions, 0.067 M , pH 7.8). The CHCl, solution was evaporated, and from the residue the hydrochloride was prepared. 2'-Ethyl-2-methyl-2-(2-rnethylthioethylamino)propionanilide (4)
742
Notes
Journal of Medicinal Chemistry, 19 73, Vol. 16, No. 6
+I tl
+I
D O
wrr-cc
or-
3 3
+I
i - s
and 2‘-Ethyl-2-methyl-3-(2-methylthioethylamino)propionanilide (5). A mixture of 11 (13.5 g, 0.0500 mol) and MeSC,H,NH,” (17.2 g, 0.189 mol) in 95% EtOH (25 ml) was allowed to reflux for 8 hr under argon. Solvent and excess amine were evaporated in vacuo; the residue was dissolved in 1M HCl and washed (Et,O). The acid solution was alkalinized (7 M NaOH), extracted (CHCl,), and evaporated. The residue (5.5 g, 0.196 mol, 39%) was partitioned between Et,O and phosphate buffer (0.067 M , pH 7.0).”>” A determination of distribution coefficients” ( K ) for the two components, brought about by extracting a buffer solution (30 ml) of a small amount of the residue with consecutive volumes of Et,O (10-ml portions), gave K , = 23 and K , = 2.9. The remainder of the residue was separated into its components by a four-funnel countercurrent procedure, using Et,O (50 ml) and buffer (400ml) in each extraction. The resulting two fractions were each reextracted according to the same pattern. Thus was obtained pure 4 (2.50 g, 8.90 mmol, 18%) and pure 5 (1.55 g, 5.52 mmol, 11%). Each fraction was converted to its hydrochloride. Compound 5 was also prepared in the following way. A mixture of 12 (7.24 g, 0.0383 mol) and MeSC,H,NH,” (S.OOg, 0.0548 mol) in MeOH (21 ml) and water (8 ml) was allowed to reflux under argon for 96 hr.After evaporation of solvent and excess amine, the residue was dissolved (1 M HCl) and thoroughly washed (Et,O). The acid solution was made alkaline (7 M NaOH) and exhaustively extracted (Et,O). After drying (Na,SO,) and evaporation, an oil was obtained from which a hydrogen sulfate was derived. A hydrochloride was also prepared and found identical with the one described above (mixture melting point). 2-(2-Methylthioethylamino)-2’,6’-propionoxylidide (6). This compound was obtained by the method used for I from 2-bromo2’,6‘-propiono~ylidide~~ and MeSC,H,NH,.” The method of Karrer, et al.,lz for the oxidation of sulfides to the corresponding sulfoxides was utilized for the following com(7). pounds. 2’-Ethyl-2-(2-methylsulfinylethylamino)propionaNlide Prepared from 1, a hydrogen sulfate was obtained. 2’Ethyl-2-(Nmethylsulfinylethy1amino)propionanilide (8). Prepared from 2, a hydrogen oxalate was obtained. Rat Sciatic Nerve Block. Solutions (0.20 ml) containing 5,10, 20, 30, or 40 mg/ml of the hydrochloride or an equivalent amount of another salt in saline were injected around the sciatic nerve at the midpoint of the femur of female Wistar rats.” Isolated Frog Sciatic Nerve Block. The compounds, in 0.02 M concentration in a frog Ringer-type solution (cf. Takman, et al. ‘9, were tested on isolated sciatic-peroneal nerve preparations of Rana pipiens by means of the action potential t e ~ h n i q u e .The ’ ~ rate of nerve block was estimated by determining the exposure time necessary to produce a 50% reduction in the height of the action potential, and this was compared to the corresponding value for lidocaine (=l). Acute Intraperitoneal and Intravenous Toxicities. Saline solutions of the hydrochlorides (20 mg/ml) or equivalent amounts of other salts were administered to female albino mice (Charles River CD random-bred). The results are estimated and should only be looked upon as approximate LD,, values. Local Irritating Effect. Solutions, 20 and 40 mg/ml as above, were injected intradermally in female, New Zealand, white rabbits and the irritation effects were estimated from gross examination of the sites 24 hr after i n j e ~ t i 0 n . l ~
Acknowledgments. We thank Dr. A. Brandstrom, AB Hassle, Goteborg, Sweden, for his kindness in supplying us with the physical-chemical constants of Table I and Mrs. Marie Hogan for performing the statistical analyses of the biological data. References
i
B. H. Takman, G. Camougis, and N. M. Lofgren, Acta Pharm. Suecica, 6, 373 (1969). E. Merck A. G. (0.Zima and A. v. Schoor), German Patent 1,034,186 (1958). M. Frahm and K. Soehring. Arzneim.-Forsch., 7.215 (1957). R. Hotovy, J. Kapff-Walter, and L. Fiebig, Arch. Int. Pharmacodyn. m e r . , 139, 281 (1962). (a) M. Celadnk, K. PalAt, A. Sekera, and C. Vfba, Arch. Pharm. (Weinheim), 291, 3 (1958); (b) B. Dofek and C. Vrba, Collect. Czech. Chem. Commun., 25, 1596 (1960). P. Viout, R. Douville, and P. Rumpf, Bull. SOC. Chim. Fr., 1252 (1962).
JournaZ of Medicinal Chemistry, 1973, Vol. 16, No. 6
Book Reviews
(7) M. Frahm and K. Soehnng, Naunyn-Schmiedebergs Arch. Pharmakol. Exp. Pathol., 236, 11 (1959). (8) A. Briindstrom, Acta G e m . Scand., 17, 1218 (1963). (9) N. Lofgren, Ark. Kemi, MineraL Geol., 22 (18),1 (1946). (10) E. Hofstetter and A. E. Wilder Smith, Helv. Chim. Acta, 36, 1698 (1953). (11) E. Hultin,Acta Chem. Scand., 15, 1130 (1961). (12) P. Karrer, E. Scheitlin, and H. Siegrist, Helv. Chirn. Acta, 33, 1237 (1950). (13) G.Camougis and B. H. Takman in “Methods in Pharmacology,” Vol. I, A. Schwartz, Ed., AppletonCenturyCrofts, New York,
743
N. Y., 1971,Chapter 1. (14)A. P. Truant, Arch. Int. Pharmacodyn. m e r . , 115,483(1958). (15) P. P. Koelzer and K. H. Wehr, Arzneim.-Forsch., 8,181 (1958). (16) P. Bieber, Bull. SOC.Chim. Fr., 56 (1954). (17) F. Yu. Rachinskii and N. M. Slavachevskaya, Tiolovye Soedin. Med., Tr. Nauch. Konf., 1957,23 (1959). (18) E.Hultin, Acta Chem. Scand., 15,879 (1961). (19) N. Lofgren and B. Lundqvist, Sv. Kem. Tidskr., 5 8 , 2 0 6 (1946). (20) B. H. Takman, G . Camougis, and N. M. Lofgren, Acta Pharm. Suecica, 6,25 (1969).
Book Reviews The Pathology of Transcription and Translation. (Biochemistry of Disease Series, Vol. 2, 1972). Edited by Emmanuel Farber with seven contributors. Marcel Dekker, New York, N. Y. 1972.x + 176 pp. 16 X 23 cm. $10.50. The first chapter of the book, a brief examination of clearly defined lesions produced by alterations in DNA, asks more questions than it answers. However, it is a stimulating discussion of the pathology of DNA. Acidic nuclear proteins and their role in gene expression in eukaryotic cellsare discussed in the next chapter together withdis eases where gene expression appears to be implicated. This is followed by an analysis of the relationship betweenDNA damage and cell death. The remainder (and majority) of the book deals with the pathology of RNA. The authors emphasize RNA inhibition and the response of the nucleus and nucleolus, cellular lesions produced by cu-amanitin, and finally the pathology of translation. The section on the nucleus and nucleolus (Chapter 5) is the only discussion presented in what might be termed classical pathology. The most striking aspect of the book is the relationship of fundamental biochemical lesions and the observed changes in the diseased cell. As the authors point out, this is the first systematic description of how interference with the synthesis and metabolism of DNA, RNA, and protein is related to disease in higher organisms, including man. In this book the authors have successfully presented some long overdue fresh views on the subject. Investigators in all fields of medicinal chemistry will appreciate the broad scope the authors present in this work. Department of Medicinal Chemistry The University of Kansas Lawrence, Kansas 66044
Mathias P. Mertes
Biosynthesis. T. A. Geissman, Senior Reporter. Vol. 1. Specialist Periodical Report of the Chemical Society, London. 1972.viii + 249 pp. 13.5 X 21.5 cm. €6.50. This book is the first volume of a series of “Specialist Periodical Reports” dealing with the synthesis of organic compounds in living organisms. The series is intended to provide systematic and comprehensive review coverage of the progress in the major areas of chemical research. This book reviews the literature on biosynthesis published during 1970 and 1971 and consists of five chapters. The first chapter discusses in a concise but adequate manner the methodology involved in modern biosynthetic experimentation with major emphasis on isotope tracer methods. Following the introductory chapter on methodology, the book is organized into four other chapters with the following headings: Biosynthesis of Terpenoids; Biosynthesis of Triterpines, Steroids and Carotenoids; Biosynthesis of Phenolic Compounds; and Biosynthesis of Alkaloids. Each individual chapter appears to represent a comprehensive and up-to-date picture of the state of knowledge in the area of biosynthesis. However, a major lack in the book is the absence of a chapter on biosynthesis of proteins, nucleic acids, and fatty acids. While the chapter on the Biosynthesis of Alkaloids does not cover
all groups of alkaloids, due to lack of sufficient data published in 1971 as well as previous coverage in recently published books and monographs, the author reports per cent incorporation of various labeled substrat:s into alkaloids in a table form which should make this chapter a u:;eful reference. This book will be outstandingly useful not only to those working in the area of biosynthesis but will serve as an extremely useful introduction to those who wish to become acquainted with the current status of knowledge in this area of research. College of Pharmacy University of Minnesota Minneapolis, Minnesota 55455
Y. J. Abul-Hajj
The Bile Acids-Chemistry, Physiology, and Metabolism. Edited by P. P. Nab and D. Kritchevsky. Vol. I: Chemistry. Plenum Press, New York and London. 1971.xi + 372 pp. 16 X 23.3 cm.
$19.50. The bile acids are the principal end products of cholesterol metabolism and perform key roles in normal and abnormalphysiological processes. Volume I of “The Bile Acids” is the first reference to comprehensikely review the moden chemical literature of this important class of steroids. The book discusses the chemical literature through 19’70,and a second volume will discuss physiology and metabolism. Volume I includes chapters on the biosynthesis and synthesis of the bile acids; their chemical reactions, physical constants, extractioii, and chromatography; mass spectra; and the solubility and micelle formation properties of the bile acids. While the coverage of a few topics is superficial, good references are given to rnore complete sources in the literature. Many laboratory procedues and techniques are completely described. The extensive use of trivial nomenclaiure and an ambiguity of drawing angular hydrogens as methyls may be a problem to some readers. However, Volume I of “The Bile Acids” will be an indispensable reference to workers in the field. Department of Medicinal Chemistry D. S. Fullerton University of Minnesota Minneapolis, Miri nesota 55455
Methods and Techniques in Clinical Chemistry. By Paul L. Wolf, Dorothy Williams, Tashiko Tsudaka, and Leticia Acosta. Wiley, New York, N. Y.1972.xiii+ 417 pp. 16 X 23.5 cm. $11.50. Every clinical chemistry laboratory must have carefully written instructions for all of their procedures in order to minimize errors. This book represents the procedure manual for the clinical chemistry l a b oratory at Stanford University Medical Center. At least it represents the procedures iri use at the time the manuscript was turned over to
